Synthesis of heterocyclic compounds

ABSTRACT

Provided herein are intermediates and processes useful for facile synthesis of biologically active molecules.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/653,994, filed on May 31, 2012, which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to heterocyclic compounds, methods for thepreparation thereof, and compounds prepared employing same.

BACKGROUND OF THE INVENTION

N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamideor propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-amide(Vemurafenib; Zelboraf™) is effective for the treatment of various B-rafmediated diseases and conditions, including, but not limited to,metastatic melanoma, thyroid cancers and colorectal cancers (Nature,2010, 467, 596-599; New England Journal of Medicine, 2010, 363, 80). Thecompound and its synthesis have been described in PCT Patent PublicationNos. WO 2007/002433 and WO 2007/002325. There remains interest indeveloping other versatile and facile processes for the efficientpreparation of this and other biologically active molecules, especially,on an industrial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I):

The compound can be used as an intermediate for the synthesis of variousbiologically active molecules. In formula (I):

-   -   Q is F or H;    -   P¹ is hydrogen or a labile protecting group;    -   P² is an amino protecting group or hydrogen; and    -   L¹ is Br, Cl, I, R¹—SO₂O— or R²C(O)O; wherein R¹ and R² are each        independently optionally substituted aryl or optionally        substituted C₁₋₆alkyl.        In one embodiment, P¹ is H. In another embodiment, Q is F; P¹ is        H; and L¹ is Br.

In another aspect, the present invention provides a method for preparinga compound of formula (I). The method comprises contacting a compound offormula (II):

with an agent having the formula: P²—X¹ under conditions sufficient toform the compound of formula (Ia):

and contacting a compound of formula (Ia) with an agent of formula:P¹—X³ under conditions sufficient to form the compound of formula(I),wherein:

-   -   X¹ is selected from Br, Cl, I, tosyl-O—, mesyl-O—,        trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—;    -   X³ is a leaving group;    -   P¹ is hydrogen or a labile protecting group;    -   P² is an amino protecting group;    -   Q is H or F; and    -   L¹ is Br, Cl, I, R¹—SO₂O— or R²C(O)O; wherein R¹ and R² are each        independently optionally substituted aryl or optionally        substituted C₁₋₆alkyl.

In yet another aspect, the present invention provides a method forpreparing a compound of formula (III):

The method comprises

-   (i) contacting a compound of formula (I) with an agent having the    formula: Y—B(OR⁵)₂ (i.e., formula IVb) or the formula: Y—Sn(Bu)₃    (i.e., formula IVc) and a palladium or a nickel complex under    conditions sufficient to form a compound of formula (IV):

-   (ii) reacting a compound of formula (IV) with an agent of the    formula: A¹-S(O)₂—Z (i.e., formula IVa) under conditions sufficient    to form a compound of formula (IX);

and

-   (iii) removing the protecting group P² under conditions sufficient    to form the compound of formula (III),    wherein:    -   Q is H or F;    -   R⁵ is —OH, C₁₋₆alkyl or two —OR⁵ substituents together with the        boron atom to which they are attached form an optionally        substituted 5 or 6-membered ring;    -   A¹ is a leaving group;    -   Y is optionally substituted aryl or optionally substituted        heteroaryl; and    -   Z is —N(R⁶)(R⁷) or —C(R⁸)(R⁹)(R¹⁰); wherein:        -   R⁶ and R⁷ are each independently selected from the group            consisting of H, optionally substituted C₁₋₆alkyl,            optionally substituted C₃₋₈cycloalkyl, optionally            substituted C₃₋₈cycloalkylalkyl, optionally substituted            heterocycloalkyl, optionally substituted            heterocycloalkylalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            heteroaryl and optionally substituted heteroarylalkyl; or R⁶            and R⁷ taken together with the nitrogen atom to which they            are attached form a four to eight-membered ring having from            0-2 additional heteroatoms as ring members selected from N,            O or S, wherein the four to eight-membered ring is            optionally substituted; and        -   R⁸, R⁹ and R¹⁰ are each independently H, optionally            substituted C₁₋₆alkyl, optionally substituted,            C₁₋₆haloalkyl, optionally substituted C₁₋₆haloalkoxy,            optionally substituted C₃₋₈cycloalkyl, optionally            substituted C₃₋₈cycloalkylalkyl, optionally substituted            aryl, optionally substituted arylalkyl, optionally            substituted heterocycloalkyl, optionally substituted            heterocycloalkylalkyl, optionally substituted heteroaryl,            optionally substituted heteroarylalkyl or —X²R¹¹, wherein X²            is —NR¹², O or S; R¹² is H, C₁₋₆alkyl or aryl; and R¹¹ is H,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₃₋₈cycloalkyl,            C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl or            heteroarylalkyl, wherein R¹¹ is optionally substituted with            from 1 to 3 R^(e) substituents selected from halogen, —CN,            —CH═CH₂, —OH, —NH₂, —NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂,            —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,            —C(NH)NH₂, —OR^(f), —SR^(f), —OC(O)R^(f), —OC(S)R^(f),            —C(O)R^(f), —C(S)R^(f), —C(O)OR^(f), —C(S)OR^(f),            —S(O)R^(f), —S(O)₂R^(f), —C(O)NHR^(f), —C(S)NHR^(f),            —C(O)NR^(f)R^(f), —C(S)NR^(f)R^(f), —S(O)₂NHR^(f),            —S(O)₂NR^(f)R^(f), —C(NH)NHR^(f), —C(NH)NR^(f)R^(f),            —NHC(O)R^(f), —NHC(S)R^(f), —NR^(f)C(O)R^(f),            —NR^(f)C(S)R^(f), —NHS(O)₂R^(f), —NR^(f)S(O)₂R^(f),            —NHC(O)NHR^(f), —NHC(S)NHR^(f), —NR^(f)C(O)NH₂,            —NR^(f)C(S)NH₂, —NR^(f)C(O)NHR^(f), —NR^(f)C(S)NHR^(f),            —NHC(O)NR^(f)R^(f), —NHC(S)NR^(f)R^(f),            —NR^(f)C(O)NR^(f)R^(f), —NR^(f)C(S)NR^(f)R^(f),            —NHS(O)₂NHR^(f), —NR^(f)S(O)₂NH₂, —NR^(f)S(O)₂NHR^(f),            —NHS(O)₂NR^(f)R^(f), —NR^(f)S(O)₂NR^(f)R^(f) , —NHR^(f),            —NR^(f)R^(f) and R^(f), wherein R^(f) is C₁₋₆alkyl,            C₃₋₆cycloalkyl, heterocycloalkyl, heteroaryl or aryl,            wherein R^(f) is optionally substituted with from 1-3 R^(g)            substituents selected from —CN, —CH═CH₂, —OH, —NH₂, —NO₂,            —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,            —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(h), —SR^(h),            —OC(O)R^(h), —OC(S)R^(h), —C(O)R^(h), —C(S)R^(h),            —C(O)OR^(h), —C(S)OR^(h), —S(O)R^(h), —S(O)₂R^(h),            —C(O)NHR^(h) or R^(h), wherein R^(h) is C₁₋₆alkyl; or any            two of the R⁸, R⁹ and R¹⁰ groups taken together with the            carbon atom to which they are attached form a 3 to            8-membered optionally substituted non-aromatic ring having            from 0 to 2 heteroatoms selected from N, O or S.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to novel synthetic intermediates andprocesses for the large-scale preparation of compounds that have thefollowing core structure (aa):

namely,[2,6-difluoro-3-(sulfonylamino)phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)methanonecore or[2-fluoro-3-(sulfonylamino)phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)methanonecore. The wavy lines indicate the points of attachment to the remainderof the structure. In some embodiments, the 5-position of the 7-azaindolering in the core structure (aa) is occupied with the substituent Y andthe sulfonyl group is linked to the substituent Z. The variables Q, Yand Z are as defined in the Summary of the Invention and any of theembodiments as described herein. For example, the present inventionprovides synthetic methods and intermediates useful for the large scalepreparation ofN-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamidesor propane-1-sulfonic acid{3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}-amides.Advantageously, the present invention provides synthetic intermediatesand versatile processes, which allow for high efficiency, low cost andlarge-scale facile synthesis of biologically active molecules includingvemurafenib with high purity. The intermediates of the present inventioncan be readily adapted to the facile preparation of various compoundshaving core structure (aa).

Definitions

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Halogen” or “halo” refers to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” or “hydroxy” refers to the group —OH.

“Thiol” refers to the group —SH.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon,having the number of carbon atoms designated (i.e. C₁-₆ means one to sixcarbons). Representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms. Further representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. For each of the definitions herein (e.g., alkyl,alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl), when a prefixis not included to indicate the number of carbon atoms in an alkylportion, the alkyl moiety or portion thereof will have 12 or fewer mainchain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewermain chain carbon atoms. For example, C₁₋₈ alkyl refers to a straight orbranched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms andincludes, but are not limited to, C₁₋₂ alkyl, C₁₋₄ alkyl, C₂₋₆ alkyl,C₂₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₇ alkyl, C₂₋₇ alkyl and C₃₋₆alkyl. “Fluoro substituted alkyl” denotes an alkyl group substitutedwith one or more fluoro atoms, such as perfluoroalkyl, where preferablythe lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also1, 2, or 3 fluoro atoms. While it is understood that substitutions areattached at any available atom to produce a stable compound, whenoptionally substituted alkyl is an R group of a moiety such as —OR (e.g.alkoxy), —SR (e.g. thioalkyl), —NHR (e.g. alkylamino), —C(O)NHR, and thelike, substitution of the alkyl R group is such that substitution of thealkyl carbon bound to any O, S, or N of the moiety (except where N is aheteroaryl ring atom) excludes substituents that would result in any O,S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkyl carbon bound to any O, S, or N of the moiety.

The term “alkylene” by itself or as part of another substituent means alinear or branched saturated divalent hydrocarbon moiety derived from analkane having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₁₋₆ means one to six carbons; C₁₋₆ alkylene is meant toinclude methylene, ethylene, propylene, 2-methylpropylene, pentylene,hexylene and the like). C₁₋₄ alkylene includes methylene —CH₂—, ethylene—CH₂CH₂—, propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂—(CH₂)₂CH₂—, —CH₂—CH(CH₃)CH₂—, —CH₂—C(CH₃)₂—,—CH₂—CH₂CH(CH₃)—. Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer,or 6 or fewer carbon atoms being preferred in the present invention.When a prefix is not included to indicate the number of carbon atoms inan alkylene portion, the alkylene moiety or portion thereof will have 12or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms,6 or fewer main chain carbon atoms or 4 or fewer main chain carbonatoms.

“Cycloalkylalkyl” refers to an -(alkylene)-cycloalkyl group wherealkylene as defined herein has the indicated number of carbon atoms orif unspecified having six or fewer, preferably four or fewer main chaincarbon atoms; and cycloalkyl is as defined herein has the indicatednumber of carbon atoms. C₃₋₈cycloalkyl-C₁₋₂alkyl meansC₃₋₈cycloalkyl-C₁₋₂alkylene, wherein the cycloalkyl has 3 to 8 ringcarbon atoms and the alkylene has 1 or 2 carbon atoms. Exemplarycycloalkylalkyl include, e.g., cyclopropylmethylene, cyclobutylethylene,cyclobutylmethylene, and the like.

“Cycloalkyl” by itself or as part of another substituent, refers tosaturated or unsaturated, non-aromatic monocyclic, bicyclic or tricycliccarbon ring systems of 3-10, also 3-8, more preferably 3-6, ring membersper ring, such as cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,adamantyl, and the like. Cycloalkyl refers to hydrocarbon rings havingthe indicated number of ring atoms (e.g., C₃₋₈ cycloalkyl means three toeight ring carbon atoms).

“Haloalkyl,” is meant to include alkyl substituted by one to sevenhalogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁-₆haloalkyl” is meant to include trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

“Haloalkoxy” refers to a —O-haloalkyl group, where haloalkyl is asdefined herein, e. g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Alkoxy” refers to a —O-alkyl group, where alkyl is as defined herein.“Cycloalkoxy” refers to a —O-cycloalkyl group, where cycloalkyl is asdefined herein. “Fluoro substituted alkoxy” denotes alkoxy in which thealkyl is substituted with one or more fluoro atoms, where preferably thealkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that O, S, or N (except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy O. Further, where alkoxy is described as a substituent of anothermoiety, the alkoxy oxygen is not bound to a carbon atom that is bound toan O, S, or N of the other moiety (except where N is a heteroaryl ringatom), or to an alkene or alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group —NH₂.

“Alkylamino” refers to a —NH-alkyl group, where alkyl is as definedherein. Exemplary alkylamino groups include CH₃NH—, ethylamino, and thelike.

“Dialkylamino” refers to a —N(alkyl)(alkyl) group, where each alkyl isindependently as defined herein. Exemplary dialkylamino groups includedimethylamino, diethylamino, ethylmethylamino, and the like.

“Cycloalkylamino” denotes the group —NR^(dd)R^(ee), where R^(dd) andR^(ee) combine with the nitrogen to form a 5-7 membered heterocycloalkylring, where the heterocycloalkyl may contain an additional heteroatomwithin the ring, such as O, N, or S, and may also be further substitutedwith alkyl, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl or R′ as defined herein.Alternatively, “cycloalkylamino” refers to a —NH-cycloalkyl group, wherecycloalkyl is as defined herein.

“Arylamino” refers to a —NH-aryl group, where aryl is as defined herein.Exemplary arylamino groups include PhNH—, naphthylamino, and the like.

“Heteroarylamino” refers to a —NH-heteroaryl group, where heteroaryl isas defined herein. Exemplary heteroarylamino groups includepyridinyl-NH—, pyrimidinyl-amino, and the like.

“Aryl” by itself or as part of another substituent refers to amonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonmoiety containing 6 to 14 ring carbon atoms. Non-limiting examples ofunsubstituted aryl groups include phenyl, 1-naphthyl, 2-naphthyl and4-biphenyl. Exemplary aryl group, such as phenyl or naphthyl, which maybe optionally fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members.

“Arylalkyl” refers to -(alkylene)-aryl, where the alkylene group is asdefined herein and has the indicated number of carbon atoms, or ifunspecified having six or fewer main chain carbon atoms or four or fewermain chain carbon atoms; and aryl is as defined herein. For example,aryl-C₁₋₂alkyl means aryl-alkylene-, where the alkylene has 1 or 2carbon atoms. Examples of arylalkyl include benzyl, phenethyl, and thelike.

“Heteroaryl” by itself or as part of another substituent refers to amonocyclic aromatic ring structure containing 5 or 6 ring atoms, or abicyclic aromatic group having 8 to 10 atoms, containing one or more,preferably 1-4, more preferably 1-3, even more preferably 1-2,heteroatoms independently selected from the group consisting of O, S,and N. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable compound is produced. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl,oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl,triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl, benzotriazinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl,pteridinyl and thiadiazolyl. “Nitrogen containing heteroaryl” refers toheteroaryl wherein any heteroatoms are N.

“Heteroarylalkyl” refers to -(alkylene)-heteroaryl, where the alkylenegroup is as defined herein and has the indicated number of carbon atoms,or if unspecified having six or fewer main chain carbon atoms or four orfewer main chain carbon atoms; and heteroaryl is as defined herein. Forexample, heteroaryl-C₁₋₂alkyl means heteroaryl-alkylene-, where thealkylene has 1 or 2 carbon atoms. Examples of heteroarylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group that contains from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized, theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl. The heterocycloalkyl may be a monocyclic, abicyclic or a polycylic ring system of 3 to 12, preferably 4 to 10 ringatoms, more preferably 5 to 8 ring atoms, even more preferably 4-6 ringatoms in which one to five ring atoms are heteroatoms selected from —N═,—N—, —O—, —S—, —S(O)—, or —S(O)₂— and further wherein one or two ringatoms are optionally replaced by a —C(O)— group. The heterocycloalkylcan also be a heterocyclic alkyl ring fused with a cycloalkyl, an arylor a heteroaryl ring. Non limiting examples of heterocycloalkyl groupsinclude pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl,butyrolactam moiety, valerolactam moiety, imidazolidinone moiety,hydantoin, dioxolane moiety, phthalimide moiety, piperidine, 1,4-dioxanemoiety, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridine moiety,3-pyrrolinyl, thiopyranyl, pyrone moiety, tetrahydrofuranyl,tetrahydrothiophenyl, quinuclidinyl, and the like. A heterocycloalkylgroup can be attached to the remainder of the molecule through a ringcarbon or a heteroatom.

“Heterocycloalkylalkyl” refers to -(alkylene)-heterocycloalkyl, wherethe alkylene group is as defined herein and has the indicated number ofcarbon atoms, or if unspecified having six or fewer main chain carbonatoms or four or fewer main chain carbon atoms; and heterocycloalkyl isas defined herein. Examples of heterocycloalkylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, alkylene, vinyl include, but are not limited to, R′,halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′,—OC(O)R′, —OC(S)R′, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —S(O)R′,—S(O)₂R′, —C(O)NHR′, —C(S)NHR′, —C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′,—S(O)₂NR′R″, —C(NH)NHR′, —C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′,—NR′C(S)R″, —NHS(O)₂R′, —NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′,—NR′C(O)NH₂, —NR′C(S)NH₂, —NR′C(O)NHR″, —NR′C(S)NHR″, —NHC(O)NR′R″,—NHC(S)NR′R″, —NR′C(O)NR″R′″, —NR′″C(S)NR′R″, —NHS(O)₂NHR′,—NR′S(O)₂NH₂, —NR′S(O)₂NHR″, —NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, and—NR′R″ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈alkoxy, haloalkyl, haloalkoxy or C₁-₈ thioalkoxy groups, orunsubstituted aryl-C₁-₄ alkyl groups. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl. R′, R″ and R′″ can be furthersubstituted with R^(a1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1), —OC(O)R^(a1), —OC(S)R^(a1),—C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1), —C(S)OR^(a1), —S(O)R^(a1),—S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1), —C(O)NR^(a1)R^(a2),—C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1), —S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1),—C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1), —NHC(S)R^(a1), —NR^(a2)C(O)R^(a1),—NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1), —NR^(a1)S(O)₂R^(a2),—NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂, —NR^(a1)C(S)NH₂,—NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2), —NHC(O)NR^(a1)R^(a2),—NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), and —NR^(a1)R^(a2) in a numberranging from zero to (2n′+1), where n′ is the total number of carbonatoms in such group. R^(a1), R^(a2) and R each independently refer tohydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈ alkoxy,haloalkyl, haloalkoxy or C₁-₈ thioalkoxy groups, or unsubstitutedaryl-C₁-₄ alkyl groups. R^(a1), R^(a2) and R^(a3) can be furthersubstituted with R^(b1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(b1), —SR^(b1), —OC(O)R^(b1), —OC(S)R^(b1),—C(O)R^(b1), —C(S)R^(b1), —C(O)OR^(b1), —C(S)OR^(b1), —S(O)R^(b1),—S(O)₂R^(b1), —C(O)NHR^(b1), —C(S)NHR^(b1), —C(O)NR^(b1)R^(b2),—C(S)NR^(b1)R^(b2), —S(O)₂NHR^(b1), —S(O)₂NR^(b1)R^(b2), —C(NH)NHR^(b1),—C(NH)NR^(b1)R^(b2), —NHC(O)R^(b1), —NHC(S)R^(b1), —NR^(b2)C(O)R^(b1),—NR^(b1)C(S)R^(b2), —NHS(O)₂R^(b1), —NR^(b1)S(O)₂R^(b2),—NHC(O)NHR^(b1), —NHC(S)NHR^(b1), —NR^(b1)C(O)NH₂, —NR^(b1)C(S)NH₂,—NR^(b1)C(O)NHR^(b2), —NR^(b1)C(S)NHR^(b2), —NHC(O)NR^(b1)R^(b2),—NHC(S)NR^(b1)R^(b2), —NR^(b1)C(O)NR^(b2)R^(b3),—NR^(b3)C(S)NR^(b1)R^(b2), —NHS(O)₂NHR^(b1), —NR^(b1)S(O)₂NH₂,—NR^(b1)S(O)₂NHR^(b2), —NHS(O)₂NR^(b1)R^(b2),—NR^(b1)S(O)₂NR^(b2)R^(b3), —NHR^(b1), and —NR^(b1)R^(b2) in a numberranging from zero to (2p′+1), where p′ is the total number of carbonatoms in such group. R^(b1), R^(b2) and R^(b3) each independently referto hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁-₈ alkoxy,haloalkyl, haloalkoxy or C₁-₈ thioalkoxy groups, or unsubstitutedaryl-C₁-₄ alkyl groups.

Substituents for the aryl and heteroaryl groups are varied and aregenerally selected from: R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, —C(S)NHR′,—C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′,—C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′, —NR′C(S)R″, —NHS(O)₂R′,—NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′, —NR′C(O)NH₂, —NR′C(S)NH₂,—NR′C(O)NHR″, —NR′C(S)NHR″, —NHC(O)NR′R″, —NHC(S)NR′R″, —NR′C(O)NR″R′″,—NR′″C(S)NR′R″, —NHS(O)₂NHR′, —NR′S(O)₂NH₂, —NR′S(O)₂NHR″,—NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, —NR′R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl.Other suitable substituents include each of the above aryl substituentsattached to a ring atom by an alkylene tether of from 1-4 carbon atoms.R′, R″ and R′″ can be further substituted with R^(a1), halogen, —OH,—NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1),—OC(O)R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(a1)R^(a2), —C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R ^(a1),—NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), —NR^(a1)R^(a2), —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R^(a1), R^(a2) and R^(a3) are each independentlyselected from hydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆cycloalkyl, cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, aryl-C₁-₄ alkyl, or aryloxy-C₁-₄alkyl. Other suitable substituents include each of the above arylsubstituents attached to a ring atom by an alkylene tether of from 1-4carbon atoms.

When two substituents are present on adjacent atoms of a substitutedaryl or a substituted heteroaryl ring, such substituents may optionallybe replaced with a substituent of the formula -T-C(O)—(CH₂)_(q)—U—,wherein T and U are independently —NH—, —O—, —CH₂— or a single bond, andq is an integer of from 0 to 2. Alternatively, when two substituents arepresent on adjacent atoms of a substituted aryl or a substitutedheteroaryl ring, such substituents may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, when two substituents are present on adjacent atoms of asubstituted aryl or a substituted heteroaryl ring, such substituents mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁-₆ alkyl.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison andHarrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).

The term “Labile protecting group” refers to those protecting groupsthat are removable under mild conditions that do not significantlyimpact other protecting groups or the remainder of the molecule.

The term “Leaving group” has the meaning conventionally associated withit in synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy(e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

Compounds

In one aspect, the present invention provides a compound of formula (I):

wherein the substituents P¹, P², L¹ and Q are as defined in the Summaryof the Invention. In one embodiment, P¹ is H. The compounds of formula(I) are useful intermediates for the synthesis of various biologicallyactive molecules, for example, compounds of formula (III):

wherein Y is optionally substituted aryl or optionally substitutedheteroaryl; Z is optionally substituted C₁₋₆alkyl, optionallysubstituted alkylamino, optionally substituted dialkylamino, optionallysubstituted cycloalkylamino, optionally substituted arylamino,optionally substituted heteroarylamino or NH₂. Q is H or F. In oneembodiment, Q is F.

In certain embodiments of compounds of formula (I), P¹ can beselectively removed in the presence of the P² group. Selective cleavageof P¹ can be accomplished by adjusting the reaction conditions, such astemperature, pH, reaction time and so forth. In some embodiments, P¹ isa labile amino protecting group. Exemplary labile protecting groupincludes 9-fluorenylmethoxycarbonyl, t-butoxycarbonyl, trimethylsilyl ort-butyldiphenylsilyl. In a preferred embodiment, P¹ is H.

In certain embodiments of compounds of formula (I), P² is an aminoprotecting group, which is capable of forming a carbamate or an amidelinkage with the amino group to which it is attached. In someembodiments, P² is an amino protecting group selected from R³—C(O)— orR⁴O—C(O)—, wherein R³ and R⁴ are each independently selected fromC₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted. In certain instances, R³ and R⁴ areeach independently selected from C₁₋₆alkyl, aryl, heteroaryl,aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each of which is optionallysubstituted with 1-3 R^(a) groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, fluoro substituted C₁₋₆alkyl,fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy, —CN, —NO₂,—OH, C₁₋₆alkyl-OC(O)—, C₁₋₆alkyl-C(O)O— or —SiMe₃, wherein the aliphaticor aromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆alkoxy, —CN, —NO₂ or —OH. In other instances, R³ and R⁴ are eachindependently methyl, ethyl, phenyl, 2,2,2-trichloroethyl, (CH₃)₂CHC≡C—,2-trimethylsilylethyl, 1-methyl-1-phenylethyl, cyclobutyl, cyclopropyl,allyl, vinyl, 1-adamantyl, benzyl or diphenylmethyl, each of which isoptionally substituted with from 1-3 R^(a) groups. In some embodiments,R^(a) is F, Cl, Br, I, —CH₃, Phenyl, t-butyl, MeO—, —NO₂, —CN, —CF₃,CF₃O—, —OH or —CH═CH₂. In one embodiment, P² is2,6-dichlorophenylcarbonyl. In another embodiment, P² is2,5-dichlorophenylcarbonyl, 2,3-dichlorophenylcarbonyl or2,4-dichlorophenylcarbonyl. In certain embodiments, P² is phenylcarbonyloptionally substituted with from 1-2 groups independently selected fromF, Cl, Br, CN or NO₂. In some embodiments of compounds of formula (I),P² is H. All the other variables L¹, P¹ and Q are as defined in any ofthe embodiments described herein.

In some embodiments of compounds of formula (I), L¹ is Br, Cl, I,tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, R¹—SO₂O— or R²C(O)O,wherein R¹ and R² are each independently selected from aryl,aryl-C₁₋₄alkyl or C₁₋₆alkyl, each of which is optionally substitutedwith from 1-3 R^(c) substituents selected from halogen, —CH═CH₂, —CN,—OH, —NH₂, —NO₂, —C(O)OH, —C(O)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d), —SR^(d), —OC(O)R^(d), —C(O)R^(d),—C(O)OR^(d), —C(S)OR^(d), —S(O)R^(d), —S(O)₂R^(d), —C(O)NHR^(d),—C(O)NR^(d)R^(d), —S(O)₂NHR^(d), —S(O)₂NR^(d)R^(d), —C(NH)NHR^(d),—C(NH)NR^(d)R^(d), —NHC(O)R^(d), —NR^(d)C(O)R^(d), —NHS(O)₂R^(d),—NR^(d)S(O)₂R^(d), —NHC(O)NHR^(d), —NHR^(d) or —NR^(d)R^(d), whereineach R^(d) is independently selected from C₁₋₆alkyl or aryl. In someinstances, R^(d) is —CH₃, ethyl or phenyl. In some embodiments, L¹ isBr, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, CF₃C(O)O— orCH₃C(O)O—. In one embodiment, L¹ is Br or Cl. All the other variables,P¹, P² and Q are as defined in any of the embodiments described herein.

In one embodiment of compounds of formula (I), P¹ is H; and Q is F. Inanother embodiment, P¹ and Q are H. In yet another embodiment, P¹ is H;L¹ is Br or Cl; and Q is F. In a preferred embodiment of compounds offormula (I), L¹ is Br or Cl; P¹ is H; and P² is2,6-dichlorophenylcarbonyl.

Methods

In another aspect, the present invention provide a method for preparinga compound of formulas (I) and (Ia). The method comprisescontacting/reacting a compound of formula (II):

with an agent of the formula: P²—X¹ under conditions sufficient to formthe compound of formula (Ia):

and contacting/reacting a compound of formula (Ia) with an agent of theformula: P¹—X³ under conditions sufficient to form the compound offormula (I). Alternatively, compound of formula (I) can also be preparedby first reacting a compound of formula (II) with an agent of theformula: P¹—X³ to form an intermediate product, followed by reacting theintermediate product with an agent of the formula: P²—X¹. X¹ is selectedfrom Br, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—,CF₃C(O)O— or CH₃C(O)O—. X³ is a leaving group. In one embodiment, X³ isCl, Br, I, tosyl-O—, mesyl-O, CF₃S(O)₂O—, CF₃C(O)O— or CH₃C(O)O—. P¹ isa labile protecting group. In one embodiment, P¹ is9-fluorenylmethoxycarbonyl, t-butoxycarbonyl, trimethylsilyl ort-butyldiphenylsilyl. In one embodiment, P² is H. In another embodiment,P² is an amino protecting group as found in T. W. Greene and P. G. Wuts,PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006) or asdefined in any of the embodiments described herein. Q is H or F. L¹ isBr, Cl, I, R¹—SO₂O— or R²C(O)O, wherein R¹ and R² are each independentlyoptionally substituted aryl or optionally substituted C₁₋₆alkyl. In someembodiments, R¹ and R² are each independently selected from aryl,aryl-C₁₋₄alkyl or C₁₋₆alkyl, each of which is optionally substitutedwith from 1-3 R^(c) substituents, wherein each R^(d) is independentlyselected from C₁₋₆alkyl or aryl. In some instances, R^(d) is —CH₃, ethylor phenyl. In some embodiments, L¹ is Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—. In a preferredembodiment, L¹ is Br or Cl.

In some embodiments, the reactions for preparing compounds of formulas(I) or (Ia) can be carried out in the presence of a base dissolved in anorganic solvent. Some preferred bases include dimethylaminopyridine(DMAP), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) andcombinations thereof. DMAP is generally present in a catalytic amount ofabout 0.05, 0.07, 0.08, 0.1, 0.2, 0.3, 0.4 or 0.5 equivalents. TEA orDIPEA can range from about 1-5 equivalents, for example, 1.0, 2.0, 3.0,4.0 or 5.0 equivalents. The organic solvents used include, but are notlimiting to, tetrahydrofuran (THF), 2-methyl-THF, acetonitrile,dichloromethane and benzene. A preferred solvent is 2-methyl-THF. Thesolvents can be present in various volumes, e.g., 0.5, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 12 volumes.

Compounds of formula (II) can be prepared by contacting a compound offormula (V):

with a reducing agent under conditions sufficient to form the compoundsof formula (II). The variables, L¹ and Q are as defined in any of theembodiments described herein. In one embodiment, L¹ is Br and Q is F.The reducing agent may be, but is not limited to, tin chloride dihydrate(SnCl₂.2H₂O). Typically, 1-5 equivalents (e.g., 1, 2, 3, 4 or 5 eqs) ofthe reducing agent are used. The reaction can be carried out at atemperature of about 40-90° C., preferably about 50-70° C., morepreferably about 60° C. The solvents for the reaction can be2-methyl-THF or a mixture of 1:1 ethyl acetate/THF. The volumes of thesolvents can be from about 5 to 100 or about 7 to 80. In one embodiment,a compound of formula (V) is treated with 3 or 4 equivalents of SnCl₂ in80 volumes of 1;1 ethyl acetate/THF or 7 volumes of 2-methyl THF at 60°C.

Compounds of formula (V) can be prepared by reacting a compound offormula (VI):

with a compound of formula (VII):

in the presence of a metal halide, such as AlCl₃ under conditionssufficient to form the compounds of formula (V). X² is selected from Br,Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, CF₃C(O)O— orCH₃C(O)O—. The variables, L¹ and Q are as defined in any of theembodiments described herein. In a preferred embodiment, X² is Br or Cl.In one embodiment, Q is F, L¹ is Br and X² is Cl. The solvents used inthe reaction include, but are not limited to, CH₃NO₂, acetonitrile,dichloromethane, dichloroethane, benzene, toluene and combinationsthereof. In one embodiment, the solvent is dichloroethane.

In another aspect, the present invention provides a method for preparinga compound of formula (III):

In one embodiment, the method comprises coupling, sulfonylation anddeprotection steps. For example, the method comprises:

-   (i) contacting a compound of formulas (I) or (Ia) with an agent of    the formula: Y—B(OR⁵)₂ (i.e., formula IVb) or the formula: Y—Sn(Bu)₃    (i.e., formula IVc) and a palladium or a nickel complex under    conditions sufficient to form a compound of formula (IV):

-   (ii) reacting a compound of formula (IV) with an agent of the    formula: A¹-S(O)₂—Z (i.e., formula IVa) under conditions sufficient    to form a compound of formula (IX):

and

-   (iii) removing the protecting group P² under conditions sufficient    to form the compound of formula (III).

Alternatively, the compounds of formula (III) can be prepared bycarrying out sulfonylation reaction first, followed by Suzuki couplingand removing of the protecting group P². For example, the methodcomprises:

-   (i) contacting a compound of formula (I) with an agent of the    formula: A¹-S(O)₂—Z (i.e., formula IVa) under conditions sufficient    to form a compound of formula (VIII):

-   (ii) reacting a compound of formula (VIII) with an agent of the    formula (IVb): Y—B(OR⁵)₂ or formula (IVc): Y—Sn(Bu)₃ and a palladium    or a nickel complex under conditions sufficient to form a compound    of formula (IX); and-   (iii) removing the protecting group P² under conditions sufficient    to form the compound of formula (III), wherein:    -   Q is H or F;    -   P¹ and P² are as defined in any of the embodiments as described        herein;    -   R⁵ is —OH, C₁₋₆alkyl or two —OR⁵ substituents together with the        boron atom to which they are attached form an optionally        substituted 5 or 6-membered ring;    -   A¹ is a leaving group;    -   Y is optionally substituted aryl or optionally substituted        heteroaryl; and    -   Z is —N(R⁶)(R⁷) or —C(R⁸)(R⁹)(R¹⁰); wherein:        -   R⁶ and R⁷ are each independently selected from the group            consisting of H, optionally substituted C₁₋₆alkyl,            optionally substituted C₃₋₈cycloalkyl, optionally            substituted C₃₋₈cycloalkylalkyl, optionally substituted            heterocycloalkyl, optionally substituted            heterocycloalkylalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            heteroaryl and optionally substituted heteroarylalkyl; or R⁶            and R⁷ taken together with the nitrogen atom to which they            are attached form a four to eight-membered ring having from            0-2 additional heteroatoms as ring members selected from N,            O or S, wherein the four to eight-membered ring is            optionally substituted; and        -   R⁸, R⁹ and R¹⁰ are each independently H, optionally            substituted C₁₋₆alkyl, optionally substituted,            C₁₋₆haloalkyl, optionally substituted C₁₋₆haloalkoxy,            optionally substituted C₃₋₈cycloalkyl, optionally            substituted C₃₋₈cycloalkylalkyl, optionally substituted            aryl, optionally substituted arylalkyl, optionally            substituted heterocycloalkyl, optionally substituted            heterocycloalkylalkyl, optionally substituted heteroaryl,            optionally substituted heteroarylalkyl or —X²R¹¹, wherein X²            is —NR¹², O or S; R¹² is H, C₁₋₆alkyl or aryl; and R¹¹ is H,            C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, C₃₋₈cycloalkyl,            C₃₋₈cycloalkylalkyl, aryl, arylalkyl, heteroaryl or            heteroarylalkyl, wherein R¹¹ is optionally substituted with            from 1 to 3 R^(e) substituents selected from halogen, —CN,            —CH═CH₂, —OH, —NH₂, —NO₂, —C(O)OH, —C(S)OH, —C(O)NH₂,            —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂,            —C(NH)NH₂, —OR^(f), —SR^(f), —OC(O)R^(f), —OC(S)R^(f),            —C(O)R^(f), —C(S)R^(f), —C(O)OR^(f), —C(S)OR^(f),            —S(O)R^(f), —S(O)₂R^(f), —C(O)NHR^(f), —C(S)NHR^(f),            —C(O)NR^(f)R^(f), —C(S)NR^(f)R^(f), —S(O)₂NHR^(f),            —S(O)₂NR^(f)R^(f), —C(NH)NHR^(f), —C(NH)NR^(f)R^(f),            —NHC(O)R^(f), —NHC(S)R^(f), —NR^(f)C(O)R^(f),            —NR^(f)C(S)R^(f), —NHS(O)₂R^(f), —NR^(f)S(O)₂R^(f),            —NHC(O)NHR^(f), —NHC(S)NHR^(f), —NR^(f)C(O)NH₂,            —NR^(f)C(S)NH₂, —NR^(f)C(O)NHR^(f), —NR^(f)C(S)NHR^(f),            —NHC(O)NR^(f)R^(f), —NHC(S)NR^(f)R^(f),            —NR^(f)C(O)NR^(f)R^(f), —NR^(f)C(S)NR^(f)R^(f),            —NHS(O)₂NHR^(f), —NR^(f)S(O)₂NH₂, —NR^(f)S(O)₂NHR^(f),            —NHS(O)₂NR^(f)R^(f), —NR^(f)S(O)₂NR^(f)R^(f) , —NHR^(f),            —NR^(f)R^(f) and R^(f), wherein R^(f) is C₁₋₆alkyl,            C₃₋₆cycloalkyl, heterocycloalkyl, heteroaryl or aryl,            wherein R^(f) is optionally substituted with from 1-3 R^(g)            substituents selected from —CN, —CH═CH₂, —OH, —NH₂, —NO₂,            —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂,            —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(h), —SR^(h),            —OC(O)R^(h), —OC(S)R^(h), —C(O)R^(h), —C(S)R^(h),            —C(O)OR^(h), —C(S)OR^(h), —S(O)R^(h), —S(O)₂R^(h),            —C(O)NHR^(h) or R^(h), wherein R^(h) is C₁₋₆alkyl; or any            two of the R⁸, R⁹ and R¹⁰ groups taken together with the            carbon atom to which they are attached form a 3 to            8-membered optionally substituted non-aromatic ring having            from 0 to 2 heteroatoms selected from N, O or S. In some            instances, at each occurrence, at least two of the R⁸, R⁹            and R¹⁰ groups are not simultaneously hydrogen. In one            embodiment, Q is F. In another embodiment, Q is H. In yet            another embodiment, Y is 4-chlorophenyl; Z is propyl; Q is            F; R⁵ is —OH; P¹ is H; and P² is 2,6-dichlorophenylcarbonyl.

The agents Y—B(OR⁵)₂ (i.e., formula IVb) or Y—Sn(Bu)₃ (i.e., formulaIVc) are either commercially available or can be readily prepared inaccordance with the procedures described in the literature. In someembodiments, —B(OR⁵)₂ is:

In one embodiment, Y—B(OR⁵)₂ is Y—B(OH)₂. Y is as defined in any of theembodiments as described herein.

The agent A¹-S(O)₂—Z (i.e., formula IVa) is either commerciallyavailable or can be readily prepared in accordance with the proceduresdescribed in the literature. The leaving group A¹ can be Cl, Br, I,tosyl-O—, mesyl-O, CF₃S(O)₂O—, CF₃C(O)O— or CH₃C(O)O—. In oneembodiment, A¹ is Cl.

In some embodiments of compounds of formula (III), Y is selected fromphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrazinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl,2-pyrazolyl, 3-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl, each ofwhich is optionally substituted with from 1-3 R^(e) groups; or 1-3 R^(f)groups; or 1-3 R^(g) groups; or 1-3 R^(h) groups. In certain instances,R^(e) is F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, ethyl, CH₃O,EtO—, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclopropylethylamino,2-cyclopropylethylamino, 1-hydroxy-1-methylethyl, methylcarbamoyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cyclohexyloxy,4-morpholino, 4-hydroxypiperidinyl,1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl or5-methylamino-1,3,4-thiadiazol-2-yl. The other variables Q and Z are asdefined in any of the embodiments as described herein.

In some embodiments of compounds of formula (III), Y is phenyl,1-naphthyl or 2-naphthyl, each of which is optionally substituted withfrom 1-3 substituents selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂,CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,methylamino, dimethylamino, methylthio, acetoxy, acetyl,methoxycarbonyl, acetamido, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl or methylcarbamoyl. The other variables Q and Zare as defined in any of the embodiments as described herein.

In some embodiments of compounds of formula (III), Y is selected from4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-thiophenyl, 3-thiophenyl, 2-amino-quinazolin-5-yl,2-amino-quinazolin-6-yl, 2-amino-quinazolin-6-yl,2-amino-quinazolin-7-yl, 2-amino-quinazolin-8-yl, 2-oxo-6-indolinyl,2-oxo-4-indolinyl, 2-oxo-5-indolinyl, 2-oxo-7-indolinyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 1 H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-ylor 1H-indazol-7-yl, each of which is substituted with from 1 to 2substituents independently selected from F, Cl, Br, I, —CN, —OH, —CF₃,NH₂, CF₃O—, CH₃—, CH₃O, C₂H_(S)O—, —NO₂, cyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, 1-cyanocyclopropyl,1-carboxycyclopropyl, 1-carbamoylcyclopropyl,1-methoxycarbonylcyclopropyl, 1-cyanoisopropyl, 1-hydroxycyclopropyl,1-hydoxyisopropyl, cyclobutoxy, cyclopentoxy, cyclohexyloxy,4-morpholino, 4-hydroxypiperidinyl,1-piperidinyl, piperazinyl,4-methylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, azetidinyl,pyrrolidinyl, cyclopropylcarbamoyl, 5-methyl-1,2,4-oxadiazol-3-yl,5-methyl-1,3,4-oxadiazol-2yl, 5-dimethylamino-1,3,4-oxadiazol-2yl,5-methylamino-1,3,4-thiadiazol-2-yl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. In certain instances, Y is 4-chlorophenyl. Inother instances, Y is 4-pyrimidinyl or 5-pyrimidinyl, each of whichoptionally substituted with from 1, 2, or 3 substituents independentlyselected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O,—NO₂, cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl,cyclopropylamino, cyclopropylmethylamino, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, isopropyl, 1-pyrrolidinyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclopropylethylamino, 2-cyclopropylethylamino or1-hydroxy-1-methylethyl. The other variables Q and Z are as defined inany of the embodiments as described herein.

In some embodiments of compounds of formula (III), Z is 1-azetindinyl,1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl,3-oxazolidinyl, 3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl,1-pyrazolidinyl, 1-piperazinyl, 1-hexahydropyrimidinyl or1-hexahydropyridazinyl, each of which is optionally substituted withfrom 1-3 R^(e) groups. In certain instances, R^(e) is F, CH₃,methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl, propen-3-yl orCH₃(CO)(CH₃)N—. The other variables Q and Y are as defined in any of theembodiments as described herein.

In some embodiments of compounds of formula (III), Z is selected from1-azetindinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,4-thiomorpholinyl, 3-oxazolidinyl, 3-thiazolidinyl, 2-isoxazolidinyl,2-isothiazolidinyl, 1-pyrazolidinyl, 1-piperazinyl,1-hexahydropyrimidinyl or 1-hexahydropyridazinyl, each of which isoptionally substituted with from 1-2 R^(i) substituents selected from F,Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂, cyclopropyl,cyclopropylmethyl, cyclopropylamino, cyclopropylmethylamino,1-cyanocyclopropyl, methylamino, dimethylamino, methylthio, acetoxy,acetyl, methoxycarbonyl, acetamido, methylcarbamoyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-oxetanyl, 3-oxetanyl, 2-oxetanylmethyl, 3-oxetanylmethyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In certain instances,R^(i) is F, CH₃, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—,vinyl, propen-3-yl or CH₃(CO)(CH₃)N—. The other variables Q and Y are asdefined in any of the embodiments as described herein.

In some embodiments of compounds of formula (III), Z is C₁₋₆alkyl,cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl orcyclooctyl, each of which is optionally substituted with from 1-3 R^(j)groups selected from F, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—, CH₃O, —NO₂,cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In one embodiment, Z ispropyl. The other variables Q and Y are as defined in any of theembodiments as described herein.

In some embodiments of compounds of formula (III), Z is selected fromthe group consisting of cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, cycloheptyl, cyclooctyl, 1-azetindinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl 3-oxazolidinyl,3-thiazolidinyl, 2-isoxazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl,1-piperazinyl, 1-hexahydropyrimidinyl, 1-hexahydropyridazinyl,(CH₃)(CF₃CH₂)N—, cyclopropylmethylamino, sec-butyl, pentan-2-yl andpentan-3-yl, each of which is optionally substituted with from 1-2 R^(k)groups selected from F, Cl, Br, I, —CN, —OH, —CF₃, NH₂, CF₃O—, CH₃—,CH₃O, —NO₂, cyclopropyl, cyclopropylmethyl, cyclopropylamino,cyclopropylmethylamino, 1-cyanocyclopropyl, methylamino, dimethylamino,methylthio, acetoxy, acetyl, methoxycarbonyl, acetamido,methylcarbamoyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl,3-pyridylmethyl, 4-pyridylmethyl, 2-oxetanyl, 3-oxtetanyl,2-oxetanylmethyl, 3-oxetanylmethyl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrofuranylmethyl,3-tetrahydrofuranylmethyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,4-morpholinyl, 2-morpholinyl or 3-morpholinyl. In one instance, R^(k) is—F, methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH—, vinyl,propen-3-yl or CH₃(CO)(CH₃)N—. In another instance, R^(k) is —F,methoxycarbonyl, ethoxycarbonyl, —CH₃, CH₃(CO)NH— or CH₃(CO)(CH₃)N—. Inyet another instance, R^(k) is vinyl or propen-3-yl. The other variablesQ and Y are as defined in any of the embodiments as described herein.

Various palladium or nickel complexes can be used for the preparation ofcompounds of formula (III). Preferably, palladium phosphine complexesare used in the reaction. The palladium complexes include, but are notlimited to, Pd(PPh₃)₄, PdCl₂(PPh₃)₂,bis[1,2-bis(diphenylphosphino)ethane]palladium,bis(tri-t-butylphosphine)palladium,diacetobis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium (Pd₂(dba)2), Pd(OAc)₂,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), anddichloro[1,1′-bis(di-i-propyl-phosphino)ferrocene]palladium (II). In oneembodiment, the palladium complex is PdCl₂(PPh₃)₂. The palladiumcomplexes can be present between 0.01 and 0.1 equivalents, e.g., about0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1equivalents. Exemplary nickel complexes include, but are not limited to,NiCl₂(dppf), bis(tricyclohexylphosphine) nickel(II) chloride(NiCl₂(PCy₃)₂) and NiCl₂(PPh₃)₂.

The Suzuki coupling reaction can be carried out in various solvents,including, but not limiting to, toluene, dioxane, THF, 2-methyl-THF,water or a mixture thereof. In one embodiment, the reaction is carriedout in dioxane or 2-methyl-THF. The reaction can be performed at atemperature between 50-100° C., 60-90° C. or 70-85° C. In oneembodiment, the reaction is carried out using 0.025-0.05 eq ofPdCl₂(PPh₃)₂, 2-3 eq of K₂CO₃ or NaHCO₃, 1 eq of compound of formula(I), 1.5-2 eq of compound of formula (IVb), 10 volumes of dioxane and 5volumes of water.

The sulfonylation reaction can be carried out in various solventsincluding, but not limiting to, pyridine, dichloromethane, THF,acetonitrile, toluene, dioxane, 2-methyl-THF or a mixture thereof.Excess solvents can be used during the reaction, for example, thesolvents can be from 1-5 equivalents, such as 1, 1.5, 2, 2.5, 3, or 4equivalents. The temperature for the reaction can be maintained fromabout 50-110° C., e.g., 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 105 or110° C. In one embodiment, the reaction is carried out in a mixedsolvents of pyridine and 10 volumes of dioxane at about 100° C.

The deprotection reaction can be conducted by reacting a compound offormula (IX) with NH₃ dissolved in an organic solvent at a temperaturefrom about 50-110° C., e.g., 50, 55, 60, 65, 70, 80, 85, 90, 95, 100,105 or 110° C. The solvents used include, but are not limited to,methanol (MeOH), ethanol (EtOH), dimethylformamide (DMF),dimethylacetamide (DMA), THF, dimethylsulfoxide (DMSO), dioxane,isopropanol (IPA) or combinations thereof. In one embodiment, thereaction can be conducted at 55° C. in the presence of NH₃ (5 eq), MeOH(5 eq, 10 volumes) and DMA (5 volumes). In another embodiment, thereaction can be conducted at 100° C. in the presence of THF (5 volumes)and NH₃/IPA (12 eq).

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1 Preparation of(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-difluoro-3-nitro-phenyl)methanone(3)

To an 50-liter flask was added 1,2-dichloroethane (DCE, 20 L), followedby 5-bromoazaindole (1) (2 kg, 10.152 mol) to result an orange slurry.Aluminum Chloride (5.421 kg, 40.608 mol) was slowly added to the flask.The first 1.5 kg of the addition was exothermic resulting a darksolution. The rest of the AlCl₃ was added to give a reaction mixture. Tothe reaction mixture was added 2,6-difluoro-3-nitrobenzoyl chloride 2(2.25 kg, 10.125 mol) via an addition funnel over a period of 1.5 h.During the addition, the reaction temperature was maintained at or below45° C. After the addition, the reaction mixture was stirred at 50° C.overnight, cooled to room temperature (˜22° C.) and transferred into twoseparate 20 L flasks. Water (25 L) and acetonitrile (12 L) were added toa 50-liter flask and cooled to 0° C. The reaction mixture was quenchedby adding water/acetonitrile solution while keeping the temperature ator below 40° C. The mixture obtained was filtered, and the filtrate waswashed with acetonitrile:water (1:1, 2×4 L), water (4 L) andacetonitrile (4 L), followed by drying in vacuum. Compound 3 (2.948 kg,73.4% yield) was obtained. MS (ESI): M+H⁺=382.9 and 383.9. ¹H NMR(DMSO-d⁶, δ ppm): 7.55 (1H, m), 8.47 (2H, m), 8.53 (1H, d, J=2.2 Hz),8.65 (1H, d, J=2.2 Hz), 13.25 (1H, s).

Example 2 Preparation of(3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(4)

A 50-liter flask was added 2-methyl-tetrahydrofuran (2-methyl-THF) (36L), compound 3 (2.85 kg, 7.455 mol) and tin(II) chloride (5.03 kg,22.365 mol). The mixture was heated to 60° C. Upon completion, thereaction was quenched with an aqueous potassium carbonate solution(20%). The resulting mixture was filtered with celite and the solidresidue was washed with 2-methyl-THF and tetrahydrofuran (THF). Thefiltrate was washed with an aqueous NaCl solution (15 L,10%) and theorganic layer was separated. The organic layer was further washed withan aqueous NaCl solution (15 L, 20%) and concentrated on a rotovap toyield compound 4 (2.536 kg, 96.65% yield). MS (ESI): M+H⁻=353 and 354.¹H NMR (DMSO-d⁶, δ ppm): 5.22 (2H, s), 6.93 (2H, m), 8.12 (1H, s), 8.47(1H, d J=2.3 Hz), 8.54 (1H, d J-1.6 Hz), 13.2 (1H, s).

Example 3 Preparation of(3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone(5)

Compound 4 (2.5 kg, 7.114 mol) obtained from Example 2 was added into a50-liter flask and cooled to 9.3° C. To compound 4 in the 50-liter flaskwas added triethylamine (0.864 kg, 8.537 mol), followed by4-dimethylaminopyridine (DMAP) (0.087 kg, 0.7114 mol) and2,6-dichlorobenzoyl chloride (1.34 kg, 6.40 mol) in 2-methyl-THF (25 L)over a period of 2 hrs. The reaction was quenched with methanol (0.30 Lat room temperature and added an aqueous NaCl solution (12.5 L, 15%) andcelite (0.5 kg). The mixture was stirred and filtered through celite.The filtrate was concentrated and added 5 volumes of heptanes. Theresulting solution was stirred for about 1 hr and dried with sodiumsulfate (1 kg) and filtered. Compound 5 was isolated by removing thesolvents under vacuum (3.47 kg, 92.93% yield). MS (ESI): M+H⁺=524,525.8, 527.8. ¹H NMR (DMSO-d⁶, δ ppm): 5.36 (2H, s), 7.01 (2H, m), 7.68(3H, s), 8.34 (1H, brs), 8.61 (1H, brs), 8.72 (1H, d J=2.3 Hz).

Example 4 Preparation of(3-amino-2,6-difluoro-phenyl)-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone(7)

Under a nitrogen atmosphere, a 50-liter flask is charged with compound 5(1.735 kg, 3.304 mol) prepared from Example 3 in 2-methyl-THF, boronicacid 6 (0.877 kg, 5.617 mol), PdCl₂(PPh₃)₂ (0.116 kg, 0.165 mol) and anaqueous sodium bicarbonate (0.833 kg, 9.912 mol) solution (8.7 L). Thereaction mixture is degassed and heated to reflux for 7 hrs and stirredat room temperature overnight. Compound 6 (129.0 g) and PdCl₂(PPh₃)₂(6.6 g) are added again and the reaction mixture is heated to reflux foranother 5 hrs. Celite (1.735 kg) is added and the mixture is stirred for30 minutes and then filtered through a pad of celite. The residue iswashed with 2-methyl-THF. The organic layer is separated, washed with a10% NaCl aqueous solution (4 L) for three times, further washed with a20% NaCl aqueous solution, filtered, and dried over Na₂SO₄. The filtrateis concentrated by removing about 80-85% of solvent, added ethyl acetate(3.5 L) and stirred overnight. The mixture is filtered and washed withethyl acetate (2×3.5 L) twice. Compound 7, is isolated after removingthe solvents and drying at 45° C. for 48 hrs (2.765 kg, 74% yield).

Example 5 Preparation ofN-[3-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamide(9)

To a compound 7 (2.76 kg, 4.961 mol) in dioxane (25 L) is added pyridine(3.92 kg, 49.6 mol), followed by compound 8 (2.42 kg, 16.99 mol). Thereaction mixture is heated to reflux and stirred overnight. The dioxanesolvent is removed by distillation and the reaction is quenched byadding a mixture of ethyl acetate (16 L) and water (14 L). The reactionmixture is filtered and the filtrate is separated into an organic and anaqueous layer. The organic layer is washed with a 10% NaCl aqueoussolution (20 L) followed by a 20% NaCl aqueous solution (20 L). Theorganic layer is separated, stirred in the presence of activated carbon(350 g) and filtered through celite. Compound 9 is isolated by removingthe solvents under vacuum (1.81 kg, 52% yield).

Example 6 Preparation ofN-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamide(10)

To a high pressure vessel is added compound 9 (1.70 kg, 2.567 mol) inTHF (5 L), followed by an ammonia/isopropyl alcohol solution (30.80 molof ammonia in 12 L of isopropyl alcohol). The mixture is heated to 100°C. overnight. When the reaction is completed, the solvents are removedin vacuum and the residue is dissolved in isopropanol. Compound 10 isisolated and further purified by recrystallization using a mixture ofTHF (7 L) and isopropanol (14 L). Yield: 0.763 kg (60.7%).

Example 7 Preparation of(3-amino-2,6-difluoro-phenyl)-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone(7)

Compound 5 (900 g; 1.7 mol) compound 6 (375.8 g; 1.4 mol), sodiumbicarbonate (302.6 g; 2.1 mol) followed by 3-methyl-THF (9 L) and water(4.5 L) were added to the 20 L reactor and the mixture was purged withnitrogen at least for 1 h. Bis-triphenylphospino-palladium (II) chloride(60.8 g; 0.086 mol) was added and the reaction mixture was heated to70-75° C. and stirred for 2 h. The reaction mixture was cooled andfiltered over celite pad. The organic layer of the filtrate wasseparated, washed with water, and concentrated under vacuum. Theprecipitated solid was isolated by filtration and dried to providecompound 7 (953.9 g) as a brown solid (Purity=95.1%; Yield=˜100%). ¹HNMR (DMSO-d6): δ (ppm) 8.75-8.76 (d, J=2.2 Hz, 1H), 8.59 (m, 1H), 8.52(s, 1H), 7.80-7.82 (d, J=8.6 Hz, 1H), 7.69-7.71 (m, 3H), 7.54-7.56 (d,J=8.6 Hz, 2H), 6.99-7.07 (m, 2H), and 5.36 (s, 2H). MS (ESI)[M+H⁺]⁺=556.1 and 558.1.

Example 8 Preparation ofN-[3-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamide(9)

Compound 7 (800 g; 1.44 mol) and dimethylamino pyridine (7.2 g; 0.059mol), under nitrogen, were added to a 5 L three-necked-round bottomflask cooled in an ice water bath. Anhydrous pyridine (1.8 L) wascharged and the mixture was stirred at 10-15° C. until a homogeneoussolution was obtained. Propane-1-sulfonyl chloride (308 g; 2.16 mol) wasadded drop-wise from an addition funnel while keeping the reactiontemperature <20° C. and the reaction mixture was stirred at 20-25° C.for 3 h. The reaction mixture was added to a mixture of 2-methyl-THF (7L) and water (10 L) in a flask and the organic layer was separated,washed with 1N HCl (2 L) followed by brine (2 L), and dried. The residuewas azeotroped with toluene to remove the residual water to providecrude compound 9 (1116.4 g) which was used in the next step withoutpurification.

Example 9 Preparation ofN-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl]propane-1-sulfonamide(10)

Crude compound 9 and THF (6 L) were added to a 12 L round-bottom flaskand stirred until the clear solution was obtained. A solution of ammoniain methanol (1.24 L; 7M) was added and stirred for 24 h at 28-35° C. Thereaction mixture was concentrated to near dryness after with methanolwas added and concentrated at 45-50° C. The separated solid was filteredand dried at 45-50° C. under vacuum to obtain crude compound 10 (601.7g; Purity=≧95%; Yield=85.4%). Recrystallization of the crude inacetone/methanol (2:1) provided compound 10 in 74% yield with a purityof 98.5%. ¹H NMR (DMSO-d6):δ (ppm) 9.78 (s, 1H), 8.72-8.73 (d, J=2.2 Hz,1H), 8.65 (brs, 1H), 8.26 (s, 1H), 7.79-7.82 (d, J=8.5 Hz, 2H),7.57-7.61 (m, 3H), 7.28-7.32 (t, J=8.3 Hz, 1H), 2.50-2.52 (m, 2H),1.73-1.78 (m, 2H), and 0.96-0.98 (t, 3H). MS (ESI) [M+H⁺]⁺=490.1 and492.1.

All patents, patent applications and other references cited in thespecification are indicative of the level of skill of those skilled inthe art to which the invention pertains, and are incorporated byreference in their entireties, including any tables and figures, to thesame extent as if each reference had been incorporated by reference inits entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any two different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

What is claimed is:
 1. A compound of formula (I):

wherein: Q is F or H; P¹ is hydrogen or a labile protecting group; P² isan amino protecting group or hydrogen; and L¹ is Br, Cl, I, R¹—SO₂O— orR²C(O)O; wherein R¹ and R² are each independently optionally substitutedaryl or optionally substituted C₁₋₆alkyl.
 2. The compound of claim 1,wherein P¹ is —H.
 3. The compound of claim 1, wherein P¹ is selectivelycleaved in the presence of P².
 4. The compound of claim 3, wherein P¹ is9-fluorenylmethoxycarbonyl, t-butoxycarbonyl, trimethylsilyl ort-butyldiphenylsilyl.
 5. The compound of any of claims 1-4, wherein P²is an amino protecting group selected from R³—C(O)— or R⁴O—C(O)—,wherein R³ and R⁴ are each independently selected from C₁₋₆alkyl, aryl,heteroaryl, aryl-C₁₋₂ alkyl, heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each of which is optionallysubstituted.
 6. The compound of claim 5, wherein P² is —H.
 7. Thecompound of claim 5, wherein P² is 2,6-dichlorophenylcarbonyl.
 8. Thecompound of any of claims 5, wherein R³ or R⁴ is optionally substitutedwith 1-3 R^(a) groups independently selected from halogen, C₁₋₆alkyl,fluoro substituted C₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl,heteroaryl, C₁₋₆alkoxy, —CN, —NO₂, —OH, C₁₋₆alkyl-OC(O)—,C₁₋₆alkyl-C(O)O— or —SiMe₃, wherein the aliphatic or aromatic portion ofR^(a) is further optionally substituted with from 1-3 R^(b) groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂ or—OH.
 9. The compound of claim 8, wherein R^(a) is F, Cl, Br, I, —CH₃,Phenyl, t-butyl, MeO—, —NO₂, —CN, —CF₃, CF₃O—, —OH or —CH═CH₂.
 10. Thecompound of any of claims 1-9, wherein R³ and R⁴ are each independentlymethyl, ethyl, phenyl, 2,2,2-trichloroethyl, (CH₃)₂CHC≡C—,2-trimethylsilylethyl, 1-methyl-1-phenylethyl, cyclobutyl, cyclopropyl,allyl, vinyl, 1-adamantyl, benzyl or diphenylmethyl, each of which isoptionally substituted with from 1-3 R^(a) groups.
 11. The compound ofany of claims 1-10, wherein L¹ is Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, R¹—SO₂O— or R²C(O)O, wherein R¹ and R² areeach independently selected from aryl, aryl-C₁₋₄alkyl or C₁₋₆alkyl, eachof which is optionally substituted with from 1-3 R^(c) substituentsselected from halogen, —CH═CH₂, —CN, —OH, —NH₂, —NO₂, —C(O)OH, —C(O)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d),—SR^(d), —OC(O)R^(d), —C(O)R^(d), —C(O)OR^(d), —C(S)OR^(d), —S(O)R^(d),—S(O)₂R^(d), —C(O)NHR^(d), —C(O)NR^(d)R^(d), —S(O)₂NHR^(d),—S(O)₂NR^(d)R^(d), —C(NH)NHR^(d), —C(NH)NR^(d)R^(d), —NHC(O)R^(d),—NR^(d)C(O)R^(d), —NHS(O)₂R^(d), —NR^(d)S(O)₂R^(d), —NHC(O)NHR^(d),—NHR^(d) or —NR^(d)R^(d), wherein each R^(d) is independently selectedfrom C₁₋₆alkyl or aryl.
 12. The compound of claim 11, wherein L¹ is Br,Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, CF₃C(O)O— orCH₃C(O)O—.
 13. The compound of claim 1, wherein P¹ is H; P² is2,6-dichlorophenylcarbonyl; and L¹ is Br.
 14. The compound of claim 1,wherein P¹ is H; P² is H; and L¹ is Br.
 15. A method for preparing acompound of formula (Ia), said method comprising: contacting a compoundof formula (II):

with an agent of the formula: P²—X¹ under conditions sufficient to formthe compound of formula (Ia):

and wherein: X¹ is selected from Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—; P² is an aminoprotecting group; Q is H or F; and L¹ is Br, Cl, I, R¹—SO₂O— orR²C(O)O—; wherein R¹ and R² are each independently optionallysubstituted aryl or optionally substituted C₁₋₆alkyl.
 16. A method forpreparing a compound of formula (I)

said method comprising: contacting a compound of formula (II):

with an agent of the formula: P²—X¹ under conditions sufficient to formthe compound of formula (Ia):

and reacting a compound of formula (Ia) with an agent of formula: P¹—X³under conditions sufficient to form the compound of formula (I);wherein: X¹ is selected from Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—; X³ is a leavinggroup; P¹ is a labile protecting group; P² is an amino protecting group;Q is H or F; L¹ is Br, Cl, I, R¹—SO₂O— or R²C(O)O; wherein R¹ and R² areeach independently optionally substituted aryl or optionally substitutedC₁₋₆alkyl.
 17. The method of claim 15, wherein said contacting iscarried out in the presence of triethylamine and4-dimethylaminopyridine.
 18. The method of claim 15 or 16, wherein L¹ isBr.
 19. The method of claim 15 or 16, wherein P² is 2,6-dichlorophenyl;and L¹ is Br.
 20. The method of claim 15 or 16, wherein Q is F.